title: Soluble frizzled-related protein 1 is estrogen inducible in bone marrow stromal cells and suppresses the earliest events in lymphopoiesis.
abstract: It has long been known that lymphopoiesis is transiently suppressed during pregnancy, which can be experimentally simulated by estrogen treatment. We now confirm with Rag1/GFP reporter mice that early lymphoid progenitors in the lineage marker(-) c-kit(high) ScaI(+), hematopoietic stem cell-enriched fraction of bone marrow are particularly depressed in these circumstances. Hematopoietic and environmental cells are both potential hormone targets and, because of this complexity, very little is known regarding mechanisms. We have now identified soluble Frizzled-related protein (sFRP)1 as an estrogen-inducible gene in stromal cells, whose expression corresponded to inability to support lymphopoiesis. Bone-lining stromal cells express sFRP1, and the transcripts were elevated by pregnancy or estrogen injection. Estrogen receptor-alpha was essential for both lymphoid suppression and induction of the sFRP family. SFRP1 has been mainly described as an antagonist for complex Wnt signals. However, we found that sFRP1, like Wnt3a, stabilized beta-catenin and blocked early lymphoid progression. Myeloerythroid progenitors were less affected by sFRP1 in culture, which was similar to estrogen with respect to lineage specificity. Hematopoietic stem cells expressed various Frizzled receptors, which markedly declined as they differentiated to lymphoid lineage. Thus, hormonal control of early lymphopoiesis in adults might partly relate to sFRP1 levels.
authors.affiliation: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Yokota
authors.forename: Kenji
authors.initials: K
authors.lastname: Oritani
authors.forename: Karla P
authors.initials: KP
authors.lastname: Garrett
authors.forename: Taku
authors.initials: T
authors.lastname: Kouro
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishida
authors.forename: Isao
authors.initials: I
authors.lastname: Takahashi
authors.forename: Michiko
authors.initials: M
authors.lastname: Ichii
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Satoh
authors.forename: Paul W
authors.initials: PW
authors.lastname: Kincade
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kanakura
mesh_terms: D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis* / Q000502:physiology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011247:Pregnancy; D012995:Solubility; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D000099274:Frizzled-Related Proteins
chemical_list: D047628:Estrogen Receptor alpha; D006023:Glycoproteins; D006131:Growth Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D000099274:Frizzled-Related Proteins